Immunomodulation Plus Myozyme May Help Infants with Pompe Disease, But Seen to Carry Risks in Study

Ana Pena, PhD avatar

by Ana Pena, PhD |

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ERT and Pompe

Adding immunomodulatory medicines to enzyme replacement therapy (ERT) — Myozyme (alglucosidase alfa) — gives temporary but not long-term protection from antibodies that can block ERT’s effectiveness in patients with classic infantile Pompe disease.

Better immunomodulatory regimens are needed to induce long-term tolerance to ERT and, importantly, to ensure the integrity of the infant’s immune system, the researchers said.

Their study, “High Sustained Antibody Titers in Patients with Classic Infantile Pompe Disease Following Immunomodulation at Start of Enzyme Replacement Therapy,” was published in The Journal of Pediatrics.

Pompe disease is an inherited lysosomal storage disorder caused by mutations in the GAA gene, which lead to a low or no levels of activity of the enzyme acid-α-glucosidase (GAA). A buildup in cells of a sugar molecule called glycogen takes place when the GAA enzyme is deficient, damaging tissues and organs, primarily the heart and skeletal (voluntary) muscles.

Enzyme replacement therapy with Myozyme (recombinant, or lab-made, human GAA, rhGAA) has led to significant clinical benefits for patients with classic infantile Pompe disease, the most severe form of the disease.

But not all respond equally well to the therapy. In part, this may be due to the formation of anti-GAA antibodies that block Myozyme’s activity or prevent its cellular uptake, neutralizing the therapy’s effect.

Currently, it’s difficult to predict which patients are at risk of producing threatening levels of such antibodies.

A study, published in 2012, reported that an immunomodulatory regimen including Rituxan/MabThera (rituximab), methotrexate and intravenous immunoglobulin was able to induce immune tolerance, meaning it offered the possibility of preventing over the long term the formation of anti-GAA neutralizing antibodies.

This treatment was seen to eliminate B-cells — the immune cells responsible for producing antibodies — at the start of Myozyme therapy, blocking antibody production for long periods.

Researchers at the Erasmus Medical Center in The Netherlands decided to examine if an identical immunomodulatory regimen would be as effective in inducing tolerance to Myozyme in a group of classic infantile Pompe disease patients referred to its hospital. 

Study data pertained to three infants — 3.1, 4.3, and 5.8 months old — who were treated four weeks with rituximab, then were started on Myozyme therapy, followed by treatment with methotrexate and intravenous immunoglobulin. ERT with Myozyme and immunomodulation continued for at least 24 months.  All showed poor head balance, and were unable to roll over; two were getting supplementary oxygen through nasal prongs. All required nasogastric tube feeding and a heart disorder known as hypertrophic cardiomyopathy.

They were monitored for the formation of anti-GAA antibodies, the loss and regrowth of B-cells, the effect of antibodies on GAA enzyme activity and cellular uptake, and clinical outcomes.

Overall, the immunomodulation regimen was well-tolerated, with most side effects being largely mild Myozyme infusion-associated reactions.

“Patients treated for at least 24 months with ERT and immunomodulation were included,” the study reports. “Immunomodulation was performed in patients, regardless of their CRIM status, who were older than 2 months of age at the start of ERT, as these might have the highest risk to develop high anti-rhGAA antibody titers.”

As expected, the number of B-cells rapidly decreased under rituximab, but returned to normal levels after it was stopped, indicating the immunomodulatory medication worked to temporarily eliminate B-cells.

 Neutralizing anti-GAA antibodies, however, begun to appear two to nine months after the start of Myozyme, rising to maximal levels at 13 to 14 months. But the high antibody levels detected were found to have only mild-to-moderate neutralizing effects on Myozyme therapy.

Analyzing cells in the lab, researchers showed that the antibodies produced by the patients had little or no ability to block GAA activity or its entry inside cells. Only one infant had a significant reduction in enzyme activity after 27 months on the therapy.

At the study’s end, all patients were ventilator-free. Heart measures — cardiac dilation, left ventricular mass index, shortening fraction — normalized completely or partly.

Motor function also improved, with the babies now learning to walk independently. All were also able to withdraw both tube feeding and oxygen ventilation before the Myozyme therapy ended.

Despite good results in these three patients, the researchers suggested that this trial be repeated in a larger number of patients with longer follow-up periods to thoroughly address the formation of neutralizing antibodies and their effects on ERT efficacy following immunomodulatory therapy.

This regimen proved to be beneficial, but the study “showed that this treatment induces immune suppression during B cell depletion rather than tolerance,” the researchers wrote.

“It will be important to optimize protocols that can provide long-term prevention of antibody formation without compromising general immunity in patients with Pompe disease treated with ERT,” they concluded.